rs376520049
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_005045.4(RELN):c.9751G>A(p.Glu3251Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3251D) has been classified as Uncertain significance.
Frequency
Consequence
NM_005045.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.9751G>A | p.Glu3251Lys | missense_variant | 60/65 | ENST00000428762.6 | |
SLC26A5-AS1 | NR_110141.1 | n.1366-14650C>T | intron_variant, non_coding_transcript_variant | ||||
RELN | NM_173054.3 | c.9751G>A | p.Glu3251Lys | missense_variant | 60/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.9751G>A | p.Glu3251Lys | missense_variant | 60/65 | 5 | NM_005045.4 | P5 | |
SLC26A5-AS1 | ENST00000422488.1 | n.1366-14650C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250908Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135648
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461748Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 727156
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3251 of the RELN protein (p.Glu3251Lys). This variant is present in population databases (rs376520049, gnomAD 0.009%). This missense change has been observed in individual(s) with neurodevelopmental disorders (PMID: 31144778, 31209962). ClinVar contains an entry for this variant (Variation ID: 475996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RELN protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
RELN-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 18, 2023 | The RELN c.9751G>A variant is predicted to result in the amino acid substitution p.Glu3251Lys. This variant was paternally inherited in an individual with Intellectual disability, autism spectrum disorder, and hypotonia (Table S1, Carraro et al. 2019. PubMed ID: 31144778; Table S5, Aspromonte et al. 2019. PubMed ID: 31209962). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-103130201-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at